Behavioral role of hypocretin (orexin) The discovery that loss of hypocretin (Hcrt, orexin) cells causes human narcolepsy has stimulated a great amount of research. However, the normal behavioral role of this peptide remains unclear. We found that Hcrt knockout (KO) mice are unable to maintain waking to work for food or water reward during the light phase of the 24 h cycle, even though by most other measures, they are less sleepy than wild type (WT) at this time.21,73,91 Surprisingly, they are unimpaired when working for reward during the dark phase, when they are sleepier than WT. They are also unimpaired when working to avoid shock in the light or in the dark phase. In WT, expression of Fos in Hcrt neurons occurs only in the light phase when working for positive reinforcement. It does not occur when WT are working for positive reinforcement in the dark phase or when working to avoid foot shock in the light or dark phases. These observations in WT are consistent with the task and light-phase specific sleepiness we observed in the KOs. Furthermore, we find that in WT, Fos is expressed in Hcrt neurons in the normal circadian light phase only when light is present. This suggests that Hcrt mediates the arousing effect of light, and can explain the lack of an arousing effect of light in narcoleptics as well as its presence both in normal humans and in pathologically sleepy humans whose Hcrt systems are intact. Fos expression reflects a summation of cellular activity over the 1-2 hour period before sacrifice and does not provide information on the time course and behavioral relations of Hcrt unit activity. Such information is critical for resolving the profound contradictions in the literature on Hcrt function. Because of te difficulty of identifying and recording from Hcrt cells in the unrestrained animal, only one such study has been reported.70 Although this study focused on the sleep cycle activity of Hcrt cells, we also noted a striking variability in the discharge of Hcrt cells during waking behaviors. This variability was not closely related to EEG changes within waking, a finding that is inconsistent with the concept that Hcrt cells are master controllers of arousal. We propose to study Hcrt unit activity during a variety of structured behaviors to determine the temporal correlates of Hcrt neuronal discharge. We will observe the activity of these neurons during both light and dark phases and during both positively and negatively reinforced behaviors. We also have the opportunity to record the correlates of Hcrt release in humans who have been implanted with microdialysis probes for clinical reasons. We will study the release of Hcrt, melanin concentrating hormone (MCH) and dopamine during structured as well as spontaneous behaviors. Only such a study can directly determine the unique characteristics of transmitter release in humans, including the relation of these transmitters to human emotions.

Public Health Relevance

We and others determined that hypocretin cell loss is the cause of human narcolepsy. We also found that hypocretin cells are lost in Parkinson's disease, accounting for several of its most troubling symptoms. In studies in mice, we found the first evidence that the hypocretin system may be responsible for the arousing and mood elevating effects of light. Our recent work, in the context of other work, suggests that hypocretin deficienc may mediate depression, one of the most common mental disorders. We propose to do the first studies of the release of dopamine, hypocretin and melanin concentrating hormone in relation to human emotion. Understanding the normal role of Hcrt will have profound implications for understanding and treating narcolepsy, Parkinson's disease and depression.